Pressure overload-induced cardiac hypertrophy due to valvular or hypertensive heart disease is a major cause of congestive heart failure in the U.S. While some degree of cardiac hypertrophy reduces wall stress, prolonged pro-hypertrophic signaling within cardiomyocytes is detrimental and contributes to the progression to heart failure. Cardiac hypertrophy is typically accompanied by the activation of Ca2+-dependent signaling pathways and the re-induction of a fetal gene expression program. Among the Ca2+-dependent pathways, the calcineurin-NFAT axis is of particular importance because it is activated at early stages of cardiac hypertrophy. In a recently published study, we have reported that STIM1 controls a newly described sarcolemmal current in adult hypertrophied cardiomyocytes that activates NFAT and further promotes cardiac hypertrophy. Stromal interaction molecule 1 (STIM1) is a dynamic transmembrane endoplasmic reticulum calcium sensor that activates plasma membrane SOCE (Store Operated Calcium Entry) channels in response to Ca2+ store depletion in many cell types. We found that STIM1 expression is elevated in neonatal rat ventricular myocytes (NRVMs) where it controls drug-inducible SOCE. This STIM1-dependent, drug-inducible SOCE was marginal in adult cardiomyocytes isolated from control hearts. However, STIM1 expression and function re-emerge in cardiomyocytes isolated from adult rats that had developed compensated cardiac hypertrophy after aortic constriction. In these adult hypertrophied cardiomyocytes, STIM1 not only controls SOCE but also an inwardly rectifying sarcolemmal current that occurs in the absence of drug-induced store depletion. Interestingly, SR Ca2+ load was not significantly decreased in hypertrophic conditions suggesting STIM1 activation can also occur in a calcium- store independent mode. By manipulating its expression, we found that STIM1 promotes the development of cardiac hypertrophy through calcineurin-NFAT activation. In addition, we found that STIM1 silencing by RNA interference abrogates the development of cardiac hypertrophy both in vitro and in vivo. We now propose to characterize the molecular pathways involved in STIM1 activation and to evaluate the physiological consequences of silencing STIM1 in rodent models of cardiac hypertrophy and heart failure. Understanding the role of specific signaling pathways involved in STIM1 activation and developing approaches to local modulation of these mechanisms may provide novel therapeutic approaches for the management of cardiac hypertrophy and heart failure.